Genetic regulation of TERT splicing affects cancer risk by altering cellular longevity and replicative potential

Oscar Florez-Vargas, Michelle Ho, Maxwell H. Hogshead, Brenen W. Papenberg, Chia-Han Lee, Kaitlin Forsythe, Kristine Jones, Wen Luo, Kedest Teshome, Cornelis Blauwendraat, Kimberly J. Billingsley, Mikhail Kolmogorov, Melissa Meredith, Benedict Paten, Raj Chari, Chi Zhang, John S. Schneekloth, Mitchell J. Machiela, Stephen J. Chanock, Shahinaz M. Gadalla, Sharon A. Savage, Sam M. Mbulaiteye and Ludmila Prokunina-Olsson ()
Additional contact information
Oscar Florez-Vargas: National Cancer Institute
Michelle Ho: National Cancer Institute
Maxwell H. Hogshead: National Cancer Institute
Brenen W. Papenberg: National Cancer Institute
Chia-Han Lee: National Cancer Institute
Kaitlin Forsythe: National Cancer Institute
Kristine Jones: Frederick National Laboratory for Cancer Research
Wen Luo: Frederick National Laboratory for Cancer Research
Kedest Teshome: Frederick National Laboratory for Cancer Research
Cornelis Blauwendraat: National Institute of Aging and National Institute of Neurological Disorders and Stroke
Kimberly J. Billingsley: National Institute of Aging and National Institute of Neurological Disorders and Stroke
Mikhail Kolmogorov: National Cancer Institute
Melissa Meredith: UC Santa Cruz Genomics Institute
Benedict Paten: UC Santa Cruz Genomics Institute
Raj Chari: Frederick National Laboratory for Cancer Research
Chi Zhang: Frederick National Laboratory for Cancer Research
John S. Schneekloth: National Cancer Institute
Mitchell J. Machiela: National Cancer Institute
Stephen J. Chanock: National Cancer Institute
Shahinaz M. Gadalla: National Cancer Institute
Sharon A. Savage: National Cancer Institute
Sam M. Mbulaiteye: National Cancer Institute
Ludmila Prokunina-Olsson: National Cancer Institute

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract The chromosome 5p15.33 region, which encodes telomerase reverse transcriptase (TERT), harbors multiple germline variants identified by genome-wide association studies (GWAS) as risk for some cancers but protective for others. Here, we characterize a variable number tandem repeat within TERT intron 6, VNTR6-1 (38-bp repeat unit), and detect a strong link between VNTR6-1 alleles (Short: 24-27 repeats, Long: 40.5-66.5 repeats) and GWAS signals rs2242652 and rs10069690 within TERT intron 4. Bioinformatics analyses reveal that rs10069690-T allele increases intron 4 retention while VNTR6-1-Long allele expands a polymorphic G-quadruplex (G4, 35-113 copies) within intron 6, with both variants contributing to variable TERT expression through alternative splicing and nonsense-mediated decay. In two cell lines, CRISPR/Cas9 deletion of VNTR6-1 increases the ratio of TERT-full-length (FL) to the alternative TERT-β isoform, promoting apoptosis and reducing cell proliferation. In contrast, treatment with G4-stabilizing ligands shifts splicing from TERT-FL to TERT-β isoform, implicating VNTR6-1 as a splicing switch. We associate the functional variants VNTR6-1, rs10069690, and their haplotypes with multi-cancer risk and age-related telomere shortening. By regulating TERT splicing, these variants may contribute to fine-tuning cellular longevity and replicative potential in the context of stress due to tissue-specific endogenous and exogenous exposures, thereby influencing the cancer risk conferred by this locus.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-56947-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56947-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-56947-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().